This application claims priority to GB9828721.2 filed Dec. 24, 1998.
This invention relates to a novel apparatus for preparing crystalline particles, particularly particles of defined particle size distribution, especially particles of therapeutically useful or carrier substances of a size suitable for inhalation therapy. There is also provided a process for preparing the same.
Industrial processes for production of many products, particularly pharmaceutical products, require the preparation of pure substances of a defined particle size distribution. Pure substances are frequently prepared by precipitation from solutions of lesser purity. When precipitation takes place relatively slowly (eg over a matter of hours), crystals are grown which are frequently of an non-uniform shape and relatively large size.
In the field of inhalation therapy, therapeutic molecules are generally desired of a particle size xe2x80x9csuitable for inhalationxe2x80x9d, which is a term generally taken to indicate an aerodynamic diameter between 1 and 10 xcexcm, especially 1 and 5 xcexcm, particularly 1 and 3 xcexcm. Carrier molecules (such as lactose) for inhaled therapeutic preparations are typically desired of a significantly larger aerodynamic diameter so that they do not penetrate into the upper respiratory tract to the same degree as the active ingredient and an aerodynamic diameter of 100 to 150 xcexcm is generally considered suitable. However this is a generalisation and for some purposes it may well be preferred to use a lower particle size for the carrier, even one comparable to that of the therapeutic substance.
Particles of the desired particle size for inhalation therapy are conventionally prepared by milling or micronisation. These processes, depending on the precise conditions adopted, are capable of generating particles distributions which include fractions having particles with the appropriate size. Milling is suitable for preparing particles of the larger size indicated above and micronisation of the smaller size indicated above. However, there are a number of disadvantages associated with milling and micronisation processes including that the fraction having the desired particle size may be relatively small, that there may be generated a significant fraction of particles that are finer than is desired (which may be deleterious eg if it affects bioavailability) and that product losses generally may be considerable. A further property of micronised products is that the surfaces of the particles generated are generally substantially amorphous (i.e. have minimal crystallinity). This may be undesirable when there exists a tendency for the amorphous regions to convert to a more stable crystalline state.
Rapid precipitation (eg by dilution of a solution with an anti-solvent) may give rise to crystalline particles which could be of suitable size, however this technique is notoriously difficult to control and has not found widespread acceptance in the pharmaceutical industry, particularly in relation to inhalation products.
The use of ultrasonic radiation to increase effectiveness of crystallisation in purification of organic substances is described in Yurhevich, et al. (1972), Primen. Ul""trazvuka Met. Protsessakh, Mosk. Inst. Stali Splavov 67, 103-106.
We have now invented a novel process and apparatus for preparing particles which overcomes or substantially mitigates one or more of the above mentioned disadvantages.
Thus according to a first aspect of the invention there is provided a process for preparing crystalline particles of substance which comprises mixing in a continuous flow cell in the presence of ultrasonic radiation a flowing solution of the substance in a liquid solvent with a flowing liquid antisolvent for said substance which is miscible with the liquid, and collecting the resultant crystalline particles generated.
A particular advantage of the process is that is capable of running continuously (subject to adequate supply of solution and anti-solvent) even if, for a particular application, it may be desired to run it only for a relatively short time.
A feature of the process is that in a steady state the concentration of dissolved substance in the mixing chamber of the flow cell remains approximately constant since the precipitating substance is replaced by the inflow of further solution. This allows the process to be run continuously and reproducibly.
According to a second aspect of the invention there is provided an apparatus for preparing crystalline particles of a substance which comprises
(i) a first reservoir of said substance dissolved in a liquid solvent;
(ii) a second reservoir of liquid antisolvent for said substance which is miscible with the liquid solvent;
(iii) a mixing chamber having first and second inlet ports and an outlet port;
(iv) means for delivering the contents of the first and second reservoirs to the mixing chamber via the first and second inlet ports respectively at independent controlled flow rate;
(v) a source of ultrasonic radiation located in the vicinity of the first inlet; and
(vi) means for collecting crystalline particles suspended in the liquid discharged from the mixing chamber at the outlet port.
Preferably the apparatus further comprises means to mix the liquids delivered to the mixing chamber via the first and second inlets. The preferred means is a stirrer. Most preferably the mixing means should be non grinding eg a non-grinding magnetic stirrer or an overhead stirrer (particularly a non-grinding magnetic stirrer).
Desirably, stirring speed will be set a level that gives efficient mixing in the mixing chamber, but without inducing vortex effects. Vortex effects are undesirably since they have a tendency to disrupt the cavitation caused by the source of ultrasonic radiation. Furthermore they may cause particle size reduction through liquid micronisation-like processes.
Desirably the means for delivering the contents of the first and second reservoirs to the mixing chamber via the first and second inlet ports respectively at independent controlled flow rate comprises one or more pumps. Preferably a pump will be provided for each of the first and second reservoirs. A range of pumps are available and may be suitable for the apparatus according to the invention. The pump may, for example, be a peristaltic pump. Pumps which are essentially non-pulsing are preferred.
The contents of the first and second reservoirs may be delivered to the mixing chamber at a range of flow rates which will be selected and optimised according to the nature of the substance, the solvent, the antisolvent and the power and frequency of the source of ultrasonic radiation. Typically flow rates will be in the range of 0.5-50 ml/min.
Preferably the outlet port of the apparatus is disposed above the inlet ports in the mixing chamber such that the liquid in the mixing chamber flows from a lower to a higher point in the chamber before exiting. This arrangement optimises mixing and allows ready balance of the rates of inflow and outflow.
Preferably the mixing chamber is substantially circular in section and the first and second inlet ports are disposed diametrically opposite each other and at the same height relative to the base of the mixing chamber. Nevertheless, it may be conceived to orientate the two inlet ports in an off-set manner in order to give some circular motion to the inflowing liquids, although this is not generally preferred.
The position of the outlet port relative to the inlet ports is believed to have an influence on the size of the crystalline particles generated. Without being limited by theory, it is believed that the greater the distance between the inlet ports and outlet port, the greater the average residence time if the particles in the flow cell, the longer the crystalline particles have to mature and hence the larger the mean particle size. However it will be appreciated that mean particle size is subject to a number of other influences.
Preferably the exit port is located approximately half way up the side of the mixing chamber.
In one particular embodiment of the invention, the apparatus according to the invention is provided with a number of optional outlet points at different heights relative to the inlet port. Fractions of differing particles size may then be xe2x80x9ctappedxe2x80x9d from the different outlet ports.
The mixing chamber may be manufactured from a range of conventional materials however these will preferably be selected so as to be unreactive with the substance, the solvent or the anti-solvent. The mixing chamber may be of any suitable size, whether of a size suitable for bench-scale preparation, industrial pilot scale preparation or industrial manufacturing scale.
Particles suspended in the liquid discharged from the mixing chamber at the outlet port may be collected by means of one of a number of conventional particle capturing techniques eg filtration or centrifugation. The preferred means is a filtration means; a wide range of suitable filters are known to persons skilled in the art. The filter may be provided with a drying facility.
Alternatively in a system where the crystallisation of the substance out of solution is essentially complete, the outflow from the mixing chamber may be fed to a spray-drying facility such that the solvent/antisolvent mixture is vaporised and the particles collected dry.
Ultrasound frequencies above around 20 kHz are generally suitable; frequencies in the range 20-25 kHz are particularly suitable, especially 22 kHz. Lower frequencies than these are generally to be avoided since they may fall within a range audible to the human ear. For a given geometry of mixing chamber, certain frequencies may be prone to cancellation. Generally this phenomenon may be avoided by modest tuning of the probe frequency.
Ultrasound power in the range 5-5000 W may be suitable (although we are not aware of any theoretical upper limit); in general smaller particles are obtainable using higher power.
The source of ultrasonic radiation will be located sufficiently close to the first inlet port such that it efficiently aids induction of precipitation of particles of substance by causing cavitation in the mixing liquids. Preferably the source is located just above the first inlet port.
The source of ultrasonic radiation may be enclosed in a protective jacket (eg one made of glass) containing a sono-radiation transmission fluid (eg silicone or olive oil).
As a further aspect of the invention we provide a process for preparing crystalline particles of a substance using an apparatus according to the invention which comprises
(i) delivering the contents of the first and second reservoirs to the mixing chamber via the first and second inlet ports respectively at independent controlled flow rate;
(ii) supplying ultrasonic radiation to the vicinity of the first inlet; and
(iii) collecting the crystalline particles suspended in the liquid discharged from the mixing chamber at the outlet port.
The process is particularly suitable for preparing particles of substances which are pharmaceutical or carrier substances suitable for inhalation therapy.
Examples of pharmaceutical substances suitable for inhalation therapy include analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen or nedocromil; antiinfectives e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g., methapyrilene; anti-inflammatories, e.g., beclomethasone, fluticasone, flunisolide, budesonide, rofleponide, mometasone or triamcinolone; antitussives, e.g., noscapine; bronchodilators, e.g., albuterol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, or (xe2x88x92)-4-amino-3,5-dichloro-xcex1-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]methyl]benzenemethanol; diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium, tiotropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; therapeutic proteins and peptides, e.g., insulin or glucagon; and salts, esters and solvates of any of the above.
Pharmaceutical substances of particular interest include fluticasone, beclomethasone, salmeterol, salbutamol or an ester, salt or solvate thereof. The substance of most interest is salmeterol xinafoate. Fluticasone propionate is also of particular interest.
Examples of carrier substances include lactose.
The solvent and antisolvent liquids will be selected so as to be appropriate for the substance. It is also necessary that they are readily miscible in the proportions employed. Suitable combinations of solvent/antisolvent include acetone/water, ethanol/IPA, methanol/IPA, methanol/water, DMF/water, DMAc/water, DMSO/water and reciprocal pairs.
1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) are also potential solvents or antisolvents which may be paired eg with ethanol. However the use of these gases in liquefied form would require the use of cold or pressurised equipment.
For generation of small particles by the process according to the invention, it is preferred that the difference between the dissolution properties of the solvent and anti-solvent be as great as possible. For reasons of industrial efficiency (particularly in order to reduce the throughput volumes of liquid) it is preferred to use concentrations of substance in solvent which are as high as possible. Nevertheless the solutions must be stable and not prone to crystallisation before discharge into the continuous flow cell. With this end in mind, it may be preferred to use the solution of the substance in the solvent at elevated temperature. It may also be preferable to cool the anti-solvent.
In order to prevent premature precipitation of the dissolved substance in the lines it will generally be desired to prime the apparatus by first pumping it with solvent. It may be preferred to prime the apparatus by pumping it with heated solvent, particularly when the dissolved substance is close to its solubility limit.
The optimum relative flow rates of substance/solvent solution and anti-solvent will generally depend on the solubility of the substance in the solvent relative to the anti-solvent. The lower this ratio is, the lower may be the flow rate of anti-solvent relative to the substance/solvent solution.
Higher flow rates of anti-solvent have a tendency to result in crystalline particles of smaller mean size.
When the substance is fluticasone propionate we prefer the solvent to be acetone and the anti-solvent to be water.
When the substance is salmeterol xinafoate we prefer the solvent to be methanol or acetone (more preferably methanol) and the anti-solvent to be water or IMS (more preferably water).
When the substance is salbutamol sulphate, we prefer the solvent to be water and the anti-solvent to be IMS.
When the substance is beclomethasone dipropionate we prefer the solvent to be IMS and the anti-solvent to be water.
When the substance is lactose we prefer the solvent to be water and the anti-solvent to be ethanol.
When the substance is budesonide, we prefer the solvent to be IMS and the anti-solvent to be water.
When the substance is formoterol fumarate or terbutaline sulphate we prefer the solvent to be methanol or acetone and the anti-solvent to be water or IMS.
As a further aspect of the invention we provide a population of particles obtainable by a process according to the invention.
Particles of pharmaceutical or carrier substances may be obtained which are suitable for use in a pharmaceutical composition for inhalation therapy, such as dry powder composition (whether containing pure drug, or drug mixed with a carrier such as lactose) or a pressurised liquid formulation (eg a formulation comprising a hydrofluoroalkane propellant such as HFA134a or HFA227).
Pressurised liquid formulations suitable for metered-dose inhalers will be retained in canisters, typically aluminium canisters (which may be plastics lined) which are provided with a metering valve of appropriate metering volume.
We also provide a pharmaceutical composition comprising a population of particles prepared according to the invention.
The advantages that the invention may possess include the fact that the process may be performed in a continuous manner without requirements for batch processing, that process may be scaled up with relative ease and that the apparatus and process are capable of producing particle size distributions of very high uniformity index.
The invention will be illustrated by reference to FIG. 1 in which mixing chamber 1 is provided with first inlet port 2 connected to first reservoir 3 containing substance dissolved in solvent and second inlet port 4 connected to second reservoir 5 containing anti-solvent. Pumps 6 and 7 deliver liquid from reservoirs 3 and 5 to mixing chamber 1 at a controlled rate. An ultrasound probe 8 is located in the vicinity of, and just above, inlet port 2. When pumps 6 and 7 are in operation, liquids from reservoirs 3 and 5 are delivered to mixing chamber 1 and are mixed with the aid of magnetic stirrer 9. Liquid containing the particles of substance thus generated flows out of the mixing chamber via exit port 10 where they are collected by means of filter 11.
In the mixing chamber used in Examples 1 and 2, the diameter was 5 cm the height was 12.5 cm, the height of the outlet above the base was 7 cm and the height of the inlets above the base was 1.5 cm.